SAN FRANCISCO – according to primary results of the Dutch COLOPEC trial presented at the 2019 GI Cancers Symposium.
Dr. Pieter J. Tanis
“Despite adjuvant systemic chemotherapy, locally advanced stage II and stage III colon cancer can give rise to metachronous peritoneal metastases in up to 25% of patients,” commented principal investigator Pieter J. Tanis, MD, PhD, a colorectal surgeon at the Academic Medical Center in Amsterdam. “These metastases are very difficult to detect, and when you detect them, they are difficult to treat.”
The 202 patients in COLOPEC, a multicenter, phase 3, randomized, controlled trial, underwent curative resection of primary colon tumors that were large (pT4 or cT4) or perforated, putting them at high risk for peritoneal metastases. All received routine adjuvant systemic chemotherapy.
At 18 months, the proportion of patients alive and free of peritoneal recurrence, assessed by laparoscopy, was 81% with addition of early postoperative oxaliplatin HIPEC and 76% without it, a nonsignificant difference.
“We couldn’t find any superiority of adjuvant HIPEC with oxaliplatin regarding peritoneal metastases–free survival in patients with T4 or perforated colon cancer,” Dr. Tanis summarized.
“We had a problem with the intention-to-treat analysis because 9% of patients already had recurrences before we performed the adjuvant HIPEC,” he added. “But I think we cannot perform an as-treated analysis in this trial because we don’t know the early recurrences in the control group.”
A symposium attendee wondered if the longer time to receiving systemic adjuvant systemic chemotherapy in the HIPEC group, a delay of about 4 weeks relative to the no-HIPEC group, was problematic and warranted consideration of neoadjuvant chemotherapy instead.
“The problem of the delay in chemotherapy, if you look in the literature, is there is no randomized trial looking at, for example, an 8- versus 12-week interval,” Dr. Tanis replied, noting that, in studies, adjuvant chemotherapy has most commonly been delayed because of patient comorbidities or surgical complications. “But you have to look very carefully at the expectation of the direct association between delay of chemotherapy and an effect. We have already looked at the disease-free survival and overall survival [in COLOPEC] and have not seen any difference … now at 23 months of follow-up,” he said.
End of the line for HIPEC?
Dr. Elin R. Sigurdson
Invited discussant Elin. R. Sigurdson, MD, PhD, a professor in the department of surgical oncology at the Fox Chase Cancer Center, Philadelphia, framed her discussion by drawing on the words of emeritus surgeon Blake Cady, MD. “ ‘In the world of surgical oncology, biology is the King, selection of cases is Queen, and the technical aspects of the surgical procedures are the Princes and Princesses who frequently try to overthrow the King and the Queen.’ ”
Staging systems, such as the Peritoneal Carcinomatosis Index, have improved patient selection. “It’s obviously very critical to assess these patients appropriately at the time of surgery, and that has influenced this study,” she maintained. “The very early recurrences I think fall into the lap of the surgeons.”
Trials in established disease have helped sort out the roles of tumor debulking and HIPEC. “In our attempt to overcome the biology of this disease, we can see that, in most of these studies, the debulking-only arm did much better than we would have thought. But controversies remain regarding both the duration of the HIPEC and the chemotherapy that we use,” Dr. Sigurdson commented. “Perhaps, as we move forward, more questions will be addressed in the near future as there are ongoing clinical trials both on our side and the European side.”
Symposium attendee Alan P. Venook, MD, of the University of California, San Francisco, noted that there have been three negative clinical trials of HIPEC in the last 3 years. “Is that enough to say enough, or do we still need to study the role of HIPEC in these patients?” he asked.
“The issue becomes, are there new possibilities in the way of new drugs in order to carry on?” Dr. Sigurdson replied. Also, “it clearly has been a learning curve in doing HIPEC, and we have failed to recognize how impactful the surgical part of HIPEC has been.”
“The trials shown today from Europe are the best-designed trials that we have, and I agree, yes, the negative trials are discouraging,” she elaborated. “But if there were drugs where the therapeutic index of giving them intraperitoneally would be beneficial, then it would be useful because it has worked in ovarian cancer, it has worked in other cancers. So hope remains. But I would argue that, in the absence of new drugs, we are getting to the point that repeating the clinical trials with those [same] drugs is not going to be positive.”
Study details
In COLOPEC, adjuvant HIPEC consisted of 30 minutes of intraperitoneal oxaliplatin plus intravenous 5-fluoruracil and leucovorin, Dr. Tanis reported at the symposium, which is sponsored by the American Gastroenterological Association, the American Society for Clinical Oncology, the American Society for Radiation Oncology, and the Society of Surgical Oncology.
HIPEC was usually performed 5-8 weeks after resection (91%) and laparoscopically (71%). Almost a fifth of patients were found to have extensive adhesions, making the procedure more difficult.
The rate of postoperative complications was 88% in the small number of patients having HIPEC at the time of resection, but only 6% in those having it 5-8 weeks after resection. A single patient developed encapsulating peritoneal sclerosis 8 months after HIPEC, requiring parenteral nutrition and surgery.
Patients in the HIPEC and control groups were similarly likely to receive adjuvant systemic chemotherapy (84% vs. 89%, P = .385), but the former had a longer time before starting this therapy (10.2 vs. 6.4 weeks, P less than .001).
Relative to counterparts in the control group, patients in the HIPEC group had a 14% reduction in risk of peritoneal recurrence or death at 18 months, but the difference was not significant (hazard ratio, 0.86; 95% confidence interval, 0.51-1.54). Findings were similar across a variety of subgroups.
In both trial groups, about two-thirds of patients in whom peritoneal metastases were detected underwent cytoreductive surgery and/or (additional) HIPEC to treat them.
“Overall, 21% of patients had peritoneal metastases detected after 23 months of follow-up, demonstrating the magnitude of this clinical problem,” noted Dr. Tanis, who reported that he had no relevant disclosures. The trial was sponsored by the Academic Medical Center, University of Amsterdam.
SOURCE: Tanis PJ et al. GI Cancers Symposium 2019, Abstract 482.